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AIDS CLINICAL ROUNDS

HIV/HCV Co-infection: The Journey of a Special Population

Susanna Naggie, MD, MHS Assistant Professor of Medicine

Director, Infectious Diseases Research Duke Clinical Research Institute

Disclosure

Commercial Research support: AbbVie Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, and Vertex Pharmaceuticals

Scientific advisor/consultant: AbbVie Pharmaceuticals, Bristol Myers Squibb. (Updated 12/11/14) **Off label use of FDA approved medications

Mr. KB 34 y/o man with HIV/HCV co-infection Diagnosed with HIV in his 20s, quite ill at the time with disseminated MAC and PCP, CD4 count was 9 He was simultaneously diagnosed with HCV Since diagnosis, he has had excellent control of his HIV

PMHx ►HIV dx 1990s

– Nadir CD4 9 – + history of OI: PCP, MAC

►HCV dx 1990s – GT1b, VL 1.2 million IU/mL – Cirrhosis dx by liver biopsy 2009 – No history of decompensation – Portal HTN with thrombocytopenia, splenomegaly and

portal gastropathy (last EGD 3/2014) – HAV and HBV immune

►AVN ►Nephrolithiasis ►Atopic Dermatitis ►Lumbar DDD

Clinical Questions to Address

►What is his prognosis? ►Why does a 34 y/o who does not drink have

cirrhosis? ►What treatment options do we have?

– Can we cure him? – What does that mean?

What is his prognosis? HIV/HCV: Natural History

D:A:D Study: Liver-Related Deaths in Persons with HIV

DAD Study Group, Arch Intern Med 2006; Lancet 2014

Mor

talit

y

31

14.5

11 9.4

34

0

5

10

15

20

25

30

35

40

AIDS Liver Cardiovascular non-AIDS cancer Other

29%

13%

15%

32%

HAART Era: Cirrhosis Risk

►Overall RR 2.11 ►Pre-HAART era

– RR 2.49

►HAART era – RR 1.72

►20-year, 30-year rates – 25%, 54%

Thein et al. AIDS 2008; 22:1979

HCV monoinfection

HIV/HCV coinfection

0.01 0.1 1 10 100

Accelerated Liver Disease in HIV

Massard et al. J Hepatol 2006; 44:S19-24 Kirk et al. Ann Intern Med 2013; 158:658-666

Hepatic Decompensation

Lo Re et al. Ann Intern Med 2014; 160

HIV-associated Non-AIDS related: “Diseases of Aging”

►Liver Fibrosis ►Cardiovascular disease ►Diabetes ►Chronic kidney disease ►Non-AIDS malignancy ►Bone disease/fractures

Why would a 34 y/o who does not drink have cirrhosis? HIV/HCV: Mechanisms of Liver Disease

Mechanisms of Fibrosis Progression

Naggie, Sulkowski. Gastroenterology 2012

The site of fibrogenesis

http://www.hindawi.com/journals/grp/2010/453563/fig1/

Gastroenterology 2008 134, 1655-1669DOI: (10.1053/j.gastro.2008.03.003) Copyright © 2008 AGA Institute Terms and Conditions

Cellular Players in Fibrogenesis

Gastroenterology 2008 134, 1655-1669DOI: (10.1053/j.gastro.2008.03.003) Copyright © 2008 AGA Institute Terms and Conditions

Pathways of hepatic stellate cell activation

HSC have HIV co-receptors

Bruno et al. Gut 2010

gp120 induces HSC cellular signaling

Bruno et al. Gut 2010

HSC may be permissive to HIV infection

Tuyama et al. Hepatology 2010

The role of a fetal morphogen

Choi et al. Intern J Biochem Cell Biol 2011

Hedgehog Signaling Pathway

Amakye et al. Nature Med 2013

Hedgehog pathway signaling following liver injury (BDL)

Omenetti et al. Lab Investigiation 2007

Hedgehog pathway signaling in HCV infection

Omenetti et al. Lab Investigiation 2007

Immunohistochemistry HIV/HCV: Immunology and Fibrosis

►Pathology specimens from liver biopsy ►Healthy controls, HIV, HCV, HIV/HCV ►Matching age, gender, race/ethnicity, fibrosis

stage, CD4 at time of biopsy, HIV suppression ►Staining: hedgehog pathway (SHH, Gli2, Ptch),

T-cell markers including CD3, CD8, CD56, CD57, CXCL16, ASMA, P16Ink4a

Hedgehog Signaling in HIV and HCV

HC HIV HCV HIV/HCV

p=0.236

p=0.007

p=0.011

Hedgehog Signaling in HIV and HCV

HC HIV HCV HIV/HCV

p=0.182

p=0.006

p<0.0001

Hedgehog Signaling in HIV/HCV

Healthy Control

HIV/HCV Infected Gli2

Targeting Hh signaling for therapy

Amakye et al. Nature Med 2013

Are Pericytes Stem Cells?

Kramann et al. Cell Stem Cell 2014

T cell presence in HIV and HCV

HC HIV HCV HIV/HCV

p<0.0001

p=0.028

p=0.001

Cytotoxic CD8 T cells

p=0.034

HC HIV HCV HIV/HCV

NK(T) cell presence in HIV and HCV

HC HIV HCV HIV/HCV

p=0.004

p=<0.0001

NKT cytokine CXCL16

HC HIV HCV HIV/HCV

p=0.026 p=0.0002

p=0.165

T cell terminal differentiation

HC HIV HCV HIV/HCV

p=0.002

p=0.017

p<0.0001

p16Ink4a aging and senescence

HC HIV HCV HIV/HCV

p<0.0001

p=0.096

p<0.0001

Take home/Future work

►Hh pathway is active in HIV mono-infection, with additive effect in co-infection

►HIV/HCV co-infection increases T cell recruitment, terminal differentiation and immunologic aging/senescence

►Peripheral (NK)T cell subsets and responsiveness to Hh signaling

►Relationship of (NK)T cell activity, dysregulation and markers of aging

►Assess Hh activity in other end organ tissue in HIV-infected patients

What treatment options do we have?

5′ UTR region

3′ UTR region 9.6 kb RNA

C A NS2 NS4B A NS5 B E2 NS3

Polyprotein IRES-mediated translation

p7 C

E1

E1 E2 NS2 NS3 NS4B 4A

Polyprotein Processing

NS5B NS5A

Core Envelope glycoproteins

Serine Protease

Serine Protease Cofactor

RNA dependent RNA polymerase

NS3-4A Protease Inhibitors

NS5B Polymerase Inhibitors

HCV Genome

Hepatitis C Virus

NS5A Inhibitors

Adapted from Naggie et al. J Antimicrob Chemother 2010

HIV/HCV: a “Special Population”

HCV Therapeutic Timeline from Interferon Approval in 1991

0

20

40

60

80

100

1991 1996 2001 2011 2013 2014

Interferon 48W

Interferon + RBV

Telaprevir & Boceprevir

Sofosbuvir & Simeprevir

Ledipasvir* Paritaprevir Ombitasvir Dasabuvir Daclatasvir

First all oral GT 2 & 3

First all oral GT 1

Issues with first wave HCV PIs

►Complex regimens ►Still require pegylated interferon and ribavirin ►~50% still require 48 weeks of treatment ►Worsened safety profile ►SVR = cure only 70% ►Significant drug interactions ►Phase II in HIV/HCV delayed by 3 years

– Still not FDA approved in HIV – Limited access in many states

New Kids on the Block in 2013

►Multi-genotypic NS3/4A PI

►QD dosing ►Second Wave PI ►Low barrier to

resistance ►+ DDI with ARVs ►Rash, photosensitivity ►HIV not a special pop

Simeprevir (TMC-435) Sofosbuvir (GS-7977) ►Pan-genotypic NS5B ►QD dosing ►Nucleotide analogue ►Exceptional barrier to

resistance ►No significant DDI ►No AE ►Approved for HIV/HCV as

special population

SMV: HCV versus HIV/HCV, genotype 1 in Clinical Trials Not head to head comparison

80 77

65

53

79 87

70

57

0102030405060708090

100

Tx Naïve Prior Partial

HCV HIV/HCV

Prior Relapse Prior Null 7/10 13/15 16/28 419/521

Antiviral Drugs Advisory Committee Meeting, FDA review, 10/24/13 C208, C216, C206, C212, HPC3007, Dieterich, 14th European AIDS Conference, 2013; Lawitz et al. NEJM 2013

SVR

Rate

42/53 206/260 15/23 9/17

SOF: HCV versus HIV/HCV in GT 1, 2, 3

89

68

95 94 93

79

89 81

89 90 91 88

0

10

20

30

40

50

60

70

80

90

100

SOF/P/R SOF/R GT 2 naïve GT 2experienced

GT 3 naïve** GT 3experienced

HCV HIV/HCV

Sust

aine

d Vi

rolo

gic R

espo

nse

Torres-Rodriguez et al., IDSA 2013 Osinusi et al., JAMA 2013;310(8):804-11; Sulkowski et al. JAMA 2014 (PHOTON-1), Lawitz et al. NEJM April 2013; Zeuzem et al NEJM May 2014, Rockstroh et al, AASLD 2014 (pooled PHOTON 1 and 2)

COSMOS: SOF/SMV no longer off label

90 94 89

81

97 94 95 94 96 95 95 92 88 94

0102030405060708090

100

Overall GT1b GT1a GT1a+Q80K GT1a-Q80KCohort 1 Cohort 2 Pooled

Lawitz et al. Lancet July 28 2014

HCV-TARGET 2.0

Jensen et al. AASLD 2014 ABST 45

SOF/P/R (N=164) SOF/SMV±RBV (N=303)

SVR4 Overall No Cirrhosis Cirrhosis GT 1a GT 1b

140 (85%)

114/127 (90%) 26/37 (70%)

-- --

269 (89%)

113/123 (92%) 156/180 (87%)* 189/222 (89%) 218/222 (95%)

Viral breakthrough 2 (1.5%) 2 (0.9%)

Relapse 21 (15.6%) 21 (9.5%)

Non-responder 1 (0.7%) 2 (0.9%)

ARV Interaction Score Card Simeprevir Sofosbuvir

ATV/r No data No data DRV/r SIM ↑; DRV ↔ SOF ↑; DRV ↔ LPV/r No data No data TPV/r No data No data EFV SIM ↓; EFV ↔ SOF ↔; EFV ↔ RPV SIM ↔; RPV ↔ SOF ↔; RPV ↔ ETV No data No data RAL SIM ↔; RAL ↔ SOF ↔; RAL ↔ ELV/cobi No data No data DLG No data No data MVC No data No data TDF SIM ↔; TFV ↔ SOF ↔; TFV ↔ Sl

ide

cour

tesy

of J

enni

fer K

iser

The new treatment paradigm

Nuc-NS5B

NS5A NS5A

nonNuc-NS5B

NS3/4A

Nuc-NS5B NS3/4A

RBV

Paritaprevir/r/Ombitasvir + Dasabuvir + RBV

Week 0 12 24 60 72

3D + WBR, N=473 SVR12

SVR12 Placebo, N=158 3D + WBR

SAPPHIRE-I: Treatment Naïve, Noncirrhotic

SAPPHIRE-II: PEG/RBV Treatment Experienced, Noncirrhotic

3D + WBR, N=297 SVR12

SVR12 Placebo, N=97 3D + WBR TURQOISE-II: Treatment Naïve and PEG/RBV Experienced, Child-Pugh A Cirrhotics

3D + WBR, N=208 SVR12

SVR12 3D + WBR, N=172

Summary SVR12: 3D+RBV 96 96 94 94 95 95

92 91 98 95 96

0

10

20

30

40

50

60

70

80

90

100

SAPPHIRE-I SAPPHIRE-II TURQUOISE-II TURQUOISE-I*

All GT1a GT1b All Rel NuR All 12W24W

No cirrhosis Tx naive

No cirrhosis NuR 55%

CP-A Cirrhosis

SAPPHIRE-I Feld et al. NEJM 2014, SAPPHIRE-II Zeuzem et al. NEJM 2014, TURQOISE-II Poordad et al. NEJM 2014; Wyles et al. AASLD 2014 Poster 1939

HIV (16% Cirrhosis) Naïve and Exp

12W 24W

Sofosbuvir/Ledipasvir ± RBV

Week 0 8 12 24 60 72

SOF/LDV ± WBR, N=431 SVR12

SVR12 SOF/LDV ± WBR, N=431

ION-1: Treatment Naïve, 16% cirrhotic

ION-2: Treatment Experienced (including triple) 20% cirrhotic

SOF/LDV ± WBR, N=220 SVR12

SVR12

ION-3: Treatment Naïve, noncirrhotic

SOF/LDV±WBR SVR12

SVR12 SOF/LDV, N=216

SOF/LDV ± WBR, N=220

N=431

Summary SVR12: SOF/LDV 99

94 94 98 98 99

93 97

86

95 100 100

0

10

20

30

40

50

60

70

80

90

100

ION-1 ION-2 ION-3 ERADICATE

12W 24W 8W -RBV +RBV

16% cirrhosis Tx naive

20% cirrhosis Triple failure 54%

Naive Non-cirrhotic

ION-1 Afdhal et al. NEJM 2014, ION-2 Afdhal et al. NEJM 2014; 370(16):1483, ION-3 Kowdley et al. NEJM; Osinusi et al. AASLD 2014, Abstract 84

Cirrhosis* -RBV +RBV 12W 24W

Cirrhosis 12W 24W 12W

HIV Naive Non-cirrhotic

Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Subjects With Chronic Genotype 1 or 4 HCV and HIV-1 Co-infection (ION-4)

ClinicalTrials.gov Identifier: NCT02073656

100 95 95 100 100

0

10

20

30

40

50

60

70

80

90

100

Tx Naïve Triple Failures

Sofosbuvir plus Daclatasvir: GT1

24W 12W +RBV -RBV

24W +RBV -RBV

Sulkowski et al. NEJM 2014; 370:211-221

N= 44 41 41 20 21

A Phase 3 Evaluation of Daclatasvir Plus Sofosbuvir in Treatment-naïve and Treatment-experienced Chronic Hepatitis C (Genotype 1, 2, 3, 4, 5, or 6) Subjects Coinfected With

Human Immunodeficiency Virus (HIV) (ALLY 2) ClinicalTrials.gov Identifier: NCT02032888

ARV Interaction Score Card Ledipasvir Daclatasvir AbbVie 3D

ATV/r ↑ LDV, ↑ATV** DCV ↑* ATV ↔; ABT450 ↑

DRV/r ↑ LDV, ↔DRV** No data DRV ↓/↑; 3D ↓

LPV/r No data No data LPV ↔; ABT450 ↑

TPV/r No data No data No data

EFV LDV ↓; EFV ↓ DCV ↓* No PK data**

RPV LDV ↔; RPV ↔ No data ABT450 ↑; RPV ↑

ETV No data No data No data

RAL LDV ↔; RAL ↔ No data 3D ↔; ↑ RAL

ELV/cobi No data No data No data

DLG No data No data No data

MVC No data No data No data

TDF LDV ↔; ↑TFV DCV ↔; TFV ↔ 3D ↔; TFV ↔ * Decrease DCV dose to 30mg QD, Increase DCV dose to 90mg QD, ** 3D + EFV led to premature study discontinuation due to toxicities

Slid

e co

urte

sy o

f Jen

nife

r Kis

er

Back to our patient 2012 – enrolled into PHOTON-1 received 6 months of sofosbuvir + WBR -SVR4, relapsed by week-12 off treatment December 2013 – labs remain reassuring with normal synthetic function, renal function, thrombocytyopenia has worsened over time now in 90s, imaging stable -Enrolled into the ION-4 with SOF/LDV X 12W -Achieved SVR12

Where do we go from here?

►Shorten treatment – 4-6 weeks ►True pangenotypic regimens ►Retreatment studies ►Acute HCV infection: ACTG 5327 ►Other Special/Unique populations:

– ESRD – Transplant – ESLD: CP B/C and decompensated – Children – Pregnant women

Acknowledgements Mentors Andrew Muir Ken Schmader Chuck Hicks John McHutchison John Guyton Mariano Garcia-Blanco Keyur Patel Hans Tillmann Leadership Chris Woods Rodger Liddle John Perfect Mary Klotman

Collaborators CHGV: David Goldstein Kevin Shianna NIAID: Shyam Kottilil Anu Osinusi Eric Meissner Diehl Laboratory: Anna Mae Diehl Steve Choi Marzena Swiderska-Syn

Funding: NIAID K23 AI096913 Duke CFAR Duke Department of Medicine AIDS Clinical Trials Group

Questions

α–smooth muscle actin

HC HIV HCV HIV/HCV

3D Phase III Studies – Viral Failure & Resistance

SVR12 Relapse Viral

Failure 2.8%

Viral Failure

VBT 15.6% (0.4%)

RAVs SAPPHIRE-I SAPPHIRE-II TURQUIOSE-II NS3/NS5A/NS5B 5 3 1 NS3/NS5A 3 1 14 NS5A only 1 1 0

87.5% with RAVS

SOF/LDV Phase III Studies – Viral Failure & Resistance

SVR12

Relapse Viral Failure 1.9%

Viral Failure

VBT 2.7% (0.05%)

RAVs ION-1 ION-2 ION-3 NS5B 0 0 0 NS5A 2 11 15 NS5A RAV at BL 2 6 9

75.6% with NS5A RAVS

ION-1 Afdhal et al. NEJM 2014, ION-2 Afdhal et al. NEJM 2014; 370(16):1483, ION-3 Kowdley et al. NEJM; Osinusi et al. AASLD 2014, Abstract 84

SOF/LDV in >500 patients with Compensated Cirrhosis

SOF/LDV, N=118 SVR12

SVR12 SOF/LDV + WBR, N=204

SOF/LDV, N=133 SVR12

SVR12 SOF/LDV + WBR, N=58

Week 0 8 12 24 60 72

Bourliere et al AASLD 2014 ABST 83

SOF/LDV in >500 patients with Compensated Cirrhosis